Potent and selective inhibitors of gelatinase-a 1. hydroxamic acid derivatives

Porter, John; Beeley, N. R. A.; Boyce, Byron A.; Mason, Barbara; Millican, Andrew T.; Millar, Kenneth; Leonard, J. C.; Morphy, J. Richard; O’Connell, James P.

doi:10.1016/s0960-894x(01)80587-4

Cited by 43 publications

(29 citation statements)

References 13 publications

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“…[38][39][40] The studied compounds are shown in Table 1. The construction of the complex structure of proMMP-2 with the studied molecules could be divided into three stages.…”

Section: Methods and Computational Detailsmentioning

confidence: 99%

Binding Affinities for a Series of Selective Inhibitors of Gelatinase-A Using Molecular Dynamics with a Linear Interaction Energy Approach

Hou

Zhang

2001

J. Phys. Chem. B

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The binding of a series of hydroxamate inhibitors with gelatinase-A is examined to evaluate the viability of calculating free energies of binding, ∆G b , utilizing molecular dynamics (MD) simulations with a linear interaction energy approach. In our simulations, a bonded model was used to represent the potentials of the catalytic zinc center. The electrostatic distribution of this model was derived using a two-stage electrostatic potential fitting calculations. The resulting bonded model was then used to generate the MD trajectories. Coulombic, van der Waals, and coordinate bond energy components determined from MD simulations of the bound and unbound inhibitors solvated in water were correlated with the free energies of binding for the 15 hydroxamate inhibitors. In the correlation process, several linear models consisted of different energy components were tested. We found that besides the usually used Coulombic and van der Waals energy terms, the introduction of a constant term could significantly improve the correlation. The best model yields an average error of 0.6 kcal/mol for the 15 binding affinities, which cover an observed range of 7.2 kcal/mol. The predictive ability of the best model was revealed by the high value of q 2 (0.854) from the leave-one-out cross-validation. To this series of inhibitors, the constant term can be treated as effective adjustment to the entropy contribution in the binding free energies. The MD simulations predicted the binding mode of the gelatinase-A with the studied inhibitors, and also provided insights into the interactions occurring in the active site and the origins of variations in ∆G b . The P 1 ′ groups of inhibitors make extensive van der Waals and hydrophobic contacts with the nonpolar side chains of four residues in the S1′ subsite, including Leu 197, Val 198, Leu 218, and Tyr 223, which directly influence the ligand binding. Hydrogen bonds between hydroxamates and gelatinase-A are very important to stabilize the inhibitors in the active site. The hydrogen bonds between the P 3 ′ group and gelatinase-A can produce more favorable electrostatic interactions.

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“…[38][39][40] The studied compounds are shown in Table 1. The construction of the complex structure of proMMP-2 with the studied molecules could be divided into three stages.…”

Section: Methods and Computational Detailsmentioning

confidence: 99%

Binding Affinities for a Series of Selective Inhibitors of Gelatinase-A Using Molecular Dynamics with a Linear Interaction Energy Approach

Hou

Zhang

2001

J. Phys. Chem. B

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“…As compared to hydroxamate compounds, phosphinic peptides were often observed to display lower potency, suggesting that the phosphinic group is a weaker zinc-chelating group than the corresponding hydroxamate group ( fig. 4) [30,31]. Another major difference between thiolate or hydroxamate and phosphinic peptides is related to their chemical structures.…”

Section: Selectivity Of Phosphinic Peptide Inhibitorsmentioning

confidence: 99%

Phosphinic peptides as zinc metalloproteinase inhibitors

Dive

Georgiadis

Matziari

et al. 2004

CMLS, Cell. Mol. Life Sci.

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Solid-phase synthesis of phosphinic peptides was introduced 10 years ago. A major application of this chemistry has been the development of potent synthetic inhibitors of zinc metalloproteases. Specific properties of the inhibitors produced in recent years are reviewed, supporting the notion that phosphinic pseudo-peptides are useful tools for studying the structural and functional biology of zinc proteases.

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“…For example, a 3-phenylpropyl group in the P1' position provides a selective inhibition of MMP-2 over that of MMP-1 and MMP-3 (e.g., 11) [79]. This discovery of the incorporation of extended P1' groups has enhanced the production of potent and selective deep pocket MMP inhibitors by medicinal chemists working in the field.…”

Section: Sulfonamide Hydroxamates and Related Structuresmentioning

confidence: 99%

Hydroxamic Acids as Pharmacological Agents

Muri¹,

Nieto²,

Sindelar³

et al. 2002

CMC

233

149

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A variety of hydroxamic acid derivatives have recently been touted for their potential use as inhibitors of hypertension, tumor growth, inflammation, infectious agents, asthma, arthritis, and more. Here we provide a comprehensive review of the basic medicinal chemistry and pharmacology of hydroxamic acid derivatives that have been examined as inhibitors of zinc metalloproteases, matrix metalloproteinases, leukotriene A(4) hydrolases, ureases, lipoxigenases, cyclooxygenases, as well as peptide deformilases.

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Potent and selective inhibitors of gelatinase-a 1. hydroxamic acid derivatives

Cited by 43 publications

References 13 publications

Binding Affinities for a Series of Selective Inhibitors of Gelatinase-A Using Molecular Dynamics with a Linear Interaction Energy Approach

Binding Affinities for a Series of Selective Inhibitors of Gelatinase-A Using Molecular Dynamics with a Linear Interaction Energy Approach

Phosphinic peptides as zinc metalloproteinase inhibitors

Hydroxamic Acids as Pharmacological Agents

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